It is well understood that diabetes is a symptomology whose primary cause is a deficiency in the supply of insulin. Two major types of diabetes are recognized--childhood-onset diabetes, which is characterized by the absence of functional beta cells normally responsible for insulin secretion from the islets of Langerhans, and adult-onset diabetes, which is characterized by a progressive debilitation of functional beta cells. The primary treatment for diabetes is, in any case, seeing to the supply of insulin in the subject, either by directly supplying animal or human insulin orally or by injection or, in the case of adult-onset diabetes, alternative or additional administration of agents, such as glyburide or tolbutamide, which stimulate the secretion of insulin by the indigenous cells.
Whatever the primary treatment regimen, it is difficult or impossible to duplicate the fine-tuned regulation of glucose metabolism mediated by endogenous insulin in the normal person. There will be periods of unduly elevated insulin levels which may lead to insulin shock or hypoglycemia, and other periods when insulin levels are too low, associated with high circulating levels of glucose in the plasma. It is, at least indirectly, these elevated circulating glucose levels which are responsible for the secondary complications of diabetes, including deterioration of the lens and retina, vascular damage leading to increases in blood flow and albumin penetration of the blood vessels, and abnormalities in the red blood cells. These deleterious effects result because the affected tissues are able to take up glucose independent of insulin, a capability not possessed by fat cells and most muscle cells. Because insulin is lacking, high levels of circulating glucose are available for easy entry into cells lacking this control mechanism.
It is also understood that the normal metabolic pathway for glucose in these noninsulin-regulated cells involves conversion by the glycolytic pathway for energy production. Glycolysis is known to proceed only when adequate levels of NAD.sup.+ are present. However, when glucose uptake levels are excessive, a large portion of the glucose is converted to sorbitol in a reaction catalyzed by aldose reductase, an enzyme whose cofactor is NADPH. The formation of sorbitol in large quantity reduces the availability of NAD.sup.+, because it serves as a hydrogen acceptor during the oxidation of sorbitol to fructose by sorbitol dehydrogenase and is thus converted to NADH.
Prevention of the deleterious effects of sorbitol by administration of inhibitors of aldose reductase is well known. A number of simple synthetic compounds which are capable of inhibiting this enzyme are currently being used or are under development. These compounds prevent the formation of the sorbitol substrate, which would otherwise deplete NAD.sup.+ when converted to fructose, and the resulting effects of NAD+ depletion on glycolysis. For example, MacLean, P., et al, Diabetic Med (1978) 2:189-193 demonstrate the effect of sorbinil on the levels of various carbohydrate metabolites in diabetic rat lens, and conclude that the aldose reductase pathway is interconnected with, e g., glycolysis by virtue of its effect on NAD.sup.+ /NADH. These inhibitors, while putatively efficacious, are foreign compounds which have the potential for serious side effects.
Travis, S.F., et al, J. Clin Invest (1971) 50:2104-2112 studied the effect of elevated glucose concentrations on human erythrocytes. It was found that addition of pyruvate to the medium prevented the accumulation of "total triose phosphates" which otherwise occured. Addition pf pyruvate presumably affects the abnormal lactate/pyruvate ratio in these cells.
The invention provides an alternative approach to the prevention of secondary diabetes symptoms which involves the administration only of natural metabolites, preferably by mouth, and in dosage forms usable as dietary supplements. These metabolites, rather than preventing the formation of sorbitol, counteract the consequences of its subsequent metabolism to fructose.